N-Methyl-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamidesas a novel class of cannabinoid receptors agonists with low CNS penetration

被引：2

作者：

Wei, Zhongyong ^{[1
]}

Yang, Hua ^{[1
]}

Liu, Ziping ^{[1
]}

Tremblay, Maxime ^{[1
]}

Johnstone, Shawn ^{[1
]}

Beha, Sara ^{[1
]}

Yue, Shi Yi ^{[1
]}

Srivastava, Sanjay ^{[1
]}

Tomaszewski, Miroslaw J. ^{[1
]}

Brown, William ^{[1
]}

Walpole, Christopher ^{[1
]}

St-Onge, Stephane ^{[2
]}

Lessard, Etienne ^{[3
]}

Archambault, Anne-Julie ^{[4
]}

Groblewski, Thierry ^{[2
]}

Page, Daniel ^{[1
]}

机构：

[1] AstraZeneca R&D, Dept Med Chem, St Laurent, PQ H4S 1Z9, Canada

[2] AstraZeneca R&D, Dept Mol Pharmacol, St Laurent, PQ H4S 1Z9, Canada

[3] AstraZeneca R&D, Dept DMPK, St Laurent, PQ H4S 1Z9, Canada

[4] AstraZeneca R&D, Dept Biosci, St Laurent, PQ H4S 1Z9, Canada

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 12期

关键词：

Cannabinoid; Tetrahydrocarbazoles; Pain; ANTIHYPERALGESIC PROPERTIES; NEUROPATHIC PAIN; CB1; RECEPTORS; BRAIN; INFLAMMATION; SYSTEM; HYPERALGESIA; ACTIVATION; RESPONSES; BINDING;

D O I：

10.1016/j.bmcl.2012.04.128

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Cannabinoid CB1 receptor agonists exhibit potent analgesic effects in rodents and humans, but their clinical utility as analgesic drugs is often limited by centrally mediated side effects. We report herein the preparation of N-methyl-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamides as a novel class of hCB(1)/hCB(2) dual agonists with attractive physicochemical properties. More specifically, (R)-N,9-dimethyl-N-(4-(methylamino)-4-oxobutyl)-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamide, displayed an extremely low level of CNS penetration (Rat Cbr/Cplasma = 0.005 or 0.5%) and was devoid of CNS side effects during pharmaco-dynamic testing. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：3884 / 3889

页数：6

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